1. Field of the Invention
This invention relates to a biocompatible carrier containing an active ingredient for introducing the active ingredient to certain target cell population in a vascular region, such as smooth muscle cells, requiring modulation to ameliorate a diseased state, particularly for the treatment of stenosis or restenosis following a vascular trauma or disease. Moreover, the invention is directed to a composition, for coating an implantable device, containing actinomycin D, or analogs and derivatives thereof.
2. Description of the Background
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress the atherosclerotic plaque of the lesion against the inner wall of the artery to dilate the lumen. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient""s vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, an expandable, intraluminal prosthesis, one example of which includes a stent, is implanted in the lumen to maintain the vascular patency.
Stents are used not only as a mechanical intervention but also as a vehicle for providing biological therapy. As a mechanical intervention, stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway. Typically stents are capable of being compressed, so that they can be inserted through small cavities via catheters, and then expanded to a larger diameter once they are at the desired location. Examples in patent literature disclosing stents which have been successfully applied in PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor. Mechanical intervention via stents, although a significant innovation in the treatment of occlusive regions, has not reduced the development of restenosis.
Biological therapy can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results.
One proposed method for medicating stents disclosed seeding the stents with endothelial cells (Dichek, D. A. et al. Seeding of Intravascular Stents With Genetically Engineered Endothelial Cells; Circulation 1989; 80: 1347-1353). Briefly, endothelial cells were seeded onto stainless steel stents and grown until the stents were covered. The cells were therefore able to be delivered to the vascular wall where they provided therapeutic proteins. Another proposed method of providing a therapeutic substance to the vascular wall included use of a heparin-coated metallic stent, whereby a heparin coating was jonically or covalently bonded to the stent. Significant disadvantages associated with the aforementioned methods include significant loss of the therapeutic substance from the body of the stent during delivery and expansion of the stent, and an absolute lack of control of the release rate of the therapeutic substance from the stent.
Another proposed method involved the use of a polymeric carrier coated onto the surface of a stent, as disclosed in U.S. Pat. No. 5,464,650 issued to Berg et al. Berg disclosed applying to a stent body a solution which included a specified solvent, a specified polymer dissolved in the solvent, and a therapeutic substance dispersed in the blend. The solvent was allowed to evaporate, leaving on the stent surface a coating of the polymer and the therapeutic substance impregnated in the polymer. Among the specified, suitable choices of polymers listed by Berg, empirical results were specifically provided for poly(caprolactone) and poly(L-lactic acid). The preferred choice of mutually compatible solvents included acetone or chloroform. As indicated by Berg, stents where immersed in the solution 12 to 15 times or sprayed 20 times. The evaporation of the solvent provided a white coating. A white coloration is generally indicative of a brittle polymeric coating. A brittle polymeric coating is an undesirable characteristic, since portions of the coating typically become detached during stent expansion. Detachment of the coating causes the quantity of the therapeutic substance to fall below a threshold level sufficient for the effective treatment of a patient.
Accordingly, it is desirable to provide an improved coating that is susceptible to expanding with a prosthesis without significant detachment from the surface of the prosthesis. It is also desirable for the polymer to be able to strongly adhere to the surface of the prosthesis, thereby preventing loss of the polymeric coating during prosthesis delivery. Other desirable features include, but are not limited to, a polymeric coating which allows for a significant control of the release rate of a therapeutic substance, a polymeric solution which need not be applied excessively to the surface of the prosthesis to form a coating of a suitable thickness, and a polymeric solution that can be uniformly applied to the surface of the prosthesis.
Local administration of therapeutic agents via stents has shown some favorable results in reducing restenosis. However, development of restenosis remains a persistent problem which has not been significantly alleviated by therapeutic substances which are currently used in the market. Accordingly, there is a great need for better and more effective therapeutic compositions, and method of administering the compositions, for inhibiting smooth muscle cell hyper-proliferation for the effective treatment of restenosis.
In accordance with one embodiment of the invention a coating for a prosthesis is provided. In one embodiment, the coating comprises an ethylene vinyl alcohol copolymer and actinomycin D or analogs or derivatives thereof. In another embodiment, the coating additionally comprises a therapeutic agent used in combination with actinomycin D or analogs or derivatives thereof The prosthesis can be a balloon-expandable stent, a self-expandable stent or a graft.
In accordance with another embodiment, a method for forming a coating onto a surface of a prosthesis, e.g., a stent, is provided. In one embodiment, the method comprises applying to the surface of the prosthesis a composition which includes an ethylene vinyl alcohol copolymer and actinomycin D, or analogs or derivatives thereof. In another embodiment, the composition additionally includes a therapeutic agent used in combination with the actinomycin D.
The composition can include a fluid. In one embodiment the fluid is a dimethylsulfoxide solution. The ethylene vinyl alcohol copolymer can constitute from about 0.1% to about 35%, the dimethylsulfoxide solution can constitute from about 59.9% to about 99.8%, and the actinomycin D, alone or in combination with the therapeutic agent, can constitute from about 0.1% to about 40% by weight of the total weight of the composition.
In accordance with another embodiment, the fluid can include the dimethylsulfoxide solution and a wetting fluid. To enhance the wetting of the composition, a suitable wetting fluid typically has a high capillary permeation. A suitably high capillary permeation corresponds to a contact angle less than about 90xc2x0. The wetting fluid can have a viscosity not greater than about 50 centipoise. The wetting fluid, accordingly, when added to the composition, reduces the viscosity of the composition. The wetting fluid should be mutually compatible with the ethylene vinyl alcohol copolymer, dimethylsulfoxide solution, and actinomycin D and should not precipitate the copolymer. Useful examples of the wetting fluid include, but are not limited to, tetrahydrofuran (THF), dimethylfornamide (DMF), 1-butanol, n-butyl acetate, dimethyl acetamide (DMAC), and mixtures thereof. In this embodiment, the ethylene vinyl alcohol copolymer can constitute from about 0.1% to about 35%, the dimethylsulfoxide can constitute from about 19.8% to about 98.8%, the wetting fluid can constitute from about 1% to about 80%, and the actinomycin D, alone or in combination with a therapeutic agent, can constitute from about 0.1% to about 40% by weight of the total weight of the composition.
The composition can be applied to the prosthesis simply by immersing the prosthesis into the composition or by spraying the composition onto the surface of the prosthesis. The dimethylsulfoxide solution or the combination of the dimethylsulfoxide solution and wetting fluid is removed from the composition which is applied to the surface of the prosthesis. The copolymer and the actinomycin D, alone or in combination with a therapeutic agent, solidifies and adheres to the surface of the prosthesis. One technique for removing the dimethylsulfoxide solution or combination of the dimethylsulfoxide solution and wetting fluid includes allowing the components to evaporate to a substantial elimination, for example, by heating the prosthesis at a predetermined temperature for a predetermined duration of time.
In accordance with another embodiment, a composition is provided for treating or inhibiting the narrowing of the blood vessel. The composition includes ethylene vinyl alcohol copolymer and actinomycin D, or analogs and derivatives thereof. The therapeutic composition is capable of being deposited in a selected region of the blood vessel to treat or inhibit the narrowing of the blood vessel.
In accordance with another embodiment, a therapeutic method is provided for inhibiting restenosis of a blood vessel by deposition into a designated region of the blood vessel an ethylene vinyl alcohol copolymer carrier impregnated with actinomycin D, or analogs and derivatives thereof.